The conservation and divergence of epigenitic reprogramming during mammalian early development

To explore how parental epigenetic information is transmitted to the next generation across mammals, we systematically investigated the epigenomes of oocytes and early embryos among human, bovine, porcine, rat, and mouse. This unprecedented dataset revealed strikingly diverse, species-specific innovation of epigenetic transition. In oocytes, DNA methylation is restricted to active gene bodies in rodents, allowing methylation of maternal imprints but not intergenic paternal imprints. Strikingly, hypermethylation also occurs in non-transcribed regions in porcine and bovine, where paternal imprints instead reside in hypomethylated, megabase-long “CpG continents (CGCs)”. Despite the presence of H3K4me3 and H3K27me3 domains in non-human oocytes, only rodent H3K27me3 survives beyond genome activation, supporting H3K27me3-mediated imprinting. Coincidently, regulatory elements are segregated away from H3K27me3 domains, the ectopic invasion of which leads to aberrant embryonic transcription. Finally, human does not fully resemble any of the rest species. Hence, mammals invent diverse epigenetic inheritance and reprogramming which center around a delicate balance in establishing imprints while protecting other regulatory regions.为探究哺乳动物亲代表观遗传信息如何向子代传递，我们系统分析了人类、牛、猪、啮齿类及小鼠的卵母细胞（oocytes）与早期胚胎（early embryos）的表观基因组（epigenomes）。这一前所未有的数据集揭示了表观遗传转变过程中显著多样且具有物种特异性的创新特征。在卵母细胞中，啮齿类的DNA甲基化（DNA methylation）仅局限于活性基因本体（active gene bodies），这使得母本印记（maternal imprints）能够发生甲基化修饰，但无法对基因间区父本印记（intergenic paternal imprints）进行甲基化。值得注意的是，猪与牛的非转录区域（non-transcribed regions）同样存在高甲基化（hypermethylation）现象，其对应的父本印记则位于低甲基化的兆碱基级（megabase-long）“CpG大陆（CGCs）”中。尽管非人卵母细胞中存在组蛋白H3第4位赖氨酸三甲基化（H3K4me3）与组蛋白H3第27位赖氨酸三甲基化（H3K27me3）结构域，但仅啮齿类的H3K27me3能够在基因组激活（genome activation）后仍维持存在，这为H3K27me3介导的印记调控提供了实验支持。巧合的是，调控元件（regulatory elements）与H3K27me3结构域相互分隔，若该结构域发生异位入侵（ectopic invasion），则会引发异常的胚胎转录（aberrant embryonic transcription）。最终研究发现，人类的表观遗传调控模式与其余所有物种均不完全一致。综上，哺乳动物演化出了多样的表观遗传继承（epigenetic inheritance）与重编程（epigenetic reprogramming）机制，其核心在于在建立印记与保护其他调控区域之间维持精妙的平衡。